Coating system for implants for increasing tissue compatibility

ABSTRACT

The invention relates to a coating system for implants comprising a metal base body, which is optionally covered with one or several intermediate layers. Said coating system comprises a coating which is disposed thereon in order to increase tissue compatibility. The coating prevents tissue irritations after implantation has an extremely high biocompatibility and has an anti-inflammatory effect. This is achieved by virtue of the fact that the coating comprises a polysaccharide layer made of a) chitosane and b) hyaluronic acid and/or hyaluronic acid derivatives.

BACKGROUND OF THE INVENTION

The present invention relates to a coating system to increase the tissuecompatibility for implants which have a metallic main body.

Implants having a metallic main body for permanent or at leastmoderate-duration residence in the human or animal body are known toresult in rejection reactions in the body, which reduce thefunctionality of the implant and the success of healing in thetreatment. This problem presents itself particularly with stents andelectrodes for stimulating body tissue. Therefore, applying coatingsystems to the implant, which increase the vascular compatibility andtherefore reduce the danger of rejection reactions of greatly varyingtypes, is known. The metallic main bodies sometimes have intermediatelayers, which are to reduce corrosive processes, as well as improve thetissue compatibility. Intermediate coatings made of amorphous siliconcarbide are an example.

Polysaccharides are known as biocompatible. Typical representatives ofthis substance class are heparin, alginate, chitosan, or hyaluronicacid. The latter two have been shown to be very compatible with thebody, and, in addition, coatings made of these components arehydrophilic and therefore the devices provided therewith may beimplanted well.

Implants coated with polysaccharides in general and hyaluronic acidspecifically and methods for their coating with hyaluronic acid areknown in numerous forms from the related art. Thus, U.S. Pat. No.6,042,876 A discloses a guide wire for implantation purposes which iscoated with such a hydrophilic polysaccharide, such as hyaluronic acidor chondroitin sulfate.

U.S. Pat. No. 4,957,744 relates to cross-linked esters of hyaluronicacid which are used for greatly varying medical and cosmetic articlesand pharmaceutical compositions. The cross-linked esters result from theesterification of multivalent alcohols with two or more carboxy groupsof hyaluronic acid. Such cross-linked esters are particularly usable inthe field of bioresorbable plastics for medical and surgical articles.

An implantable stimulation electrode, which displays elevated tissuecompatibility, is known from DE 196 30 563. This is achieved in that athin, specifically functionalized organic coating, which formsessentially the entire external surface of the stimulation electrode, isprovided, which adheres permanently to the surface lying underneath itbecause of irreversible physisorption or covalent bonding. Among otherthings, silanes and synthetic polymers such as polystyrene sulfonate,polyvinyl sulfonate, or polyallyl amine were suggested as coatingmaterials. The organic coating may also be multilayered, polyethyleneoxide or polyethylene glycol being terminated at the external surface inparticular. Furthermore, it is claimed that the organic coating containsa medicinal active ingredient, particularly an anti-inflammatorymedication, which may be delivered from the organic coating throughdiffusion or solution.

The described improvements through coating the stimulation electrode doresult in a significant reduction of the temporary stimulus thresholdincrease, but are relatively complex and therefore costly to implementand require extensive tests to evaluate the biocompatibility because ofthe synthetic nature of the materials used. Furthermore, in the case ofthe desired addition of anti-inflammatory active ingredients, it isnecessary to tailor the material properties of active ingredients andthe organic coating in which they are embedded to one another throughextensive tests.

Finally, WO 8802623 A1 relates to biomaterials having a biocompatiblesurface, among other things, the use of hyaluronic acid to manufacture abiocompatible contact lens being disclosed among multiple startingmaterials and binding mechanisms.

Insofar as the above-mentioned publications relate to coating systemsfor medical devices and particularly stents and stimulation electrodes,they have the disadvantage that the coatings achieved do not achievesufficient adhesion strength on the substrate surface, the coatingscover the fine structures of the implants unevenly, and theirapplication is very technically complex.

BRIEF SUMMARY OF THE INVENTION

An aspect of the present invention is to provide a coating system forimplants which overcomes the above-mentioned disadvantages of therelated art. In particular, the coating system is to have very highbiocompatibility and, in addition, is to have an anti-inflammatoryeffect per se. Furthermore, the coating system is to comprise as few aspossible components, which are easy to process, so that themanufacturing is simplified.

This aspect is achieved by the coating system according to the presentinvention which have a coating bound through physisorption and/orcovalent bonds. The coating covers the metallic main body and possiblyone or more intermediate layers applied to the main body. The coatingcomprises a polysaccharide layer made of

(a) chitosan and

(b) hyaluronic acid and/or hyaluronic acid derivatives.

Surprisingly, it has been shown that the application of such apolysaccharide layer contributes to a significant improvement of thetissue compatibility. Furthermore, hyaluronic acid, its derivatives, andchitosan are distinguished by their very good biocompatibility, sincethe materials are of natural origin. In addition, it has been shown thatat least hyaluronic acid and also its derivatives have an intrinsicanti-inflammatory effect and therefore may effectively prevent or atleast strongly reduce tissue irritations.

DETAILED DESCRIPTION OF THE INVENTION

Hyaluronic acid (hyaluronan) is a simple glycosaminoglycan of theextracellular matrix. It is synthesized on the surface of fibroblastsand occurs as a single glycosaminoglycan, not as a proteoglycan.Hyaluronic acid is a high-molecular-weight compound having M_(R) between50,000 and several million. The basic component of hyaluronic acid is anaminodisaccharide, synthesized from D-glucuronic acid andN-acetyl-d-glucosamine in β1-3-glycosidic bonding, which has aβ1-4-glycosidic bond to the next unit:

The unbranched chain of hyaluronic acid comprises 2,000-10,000 suchunits. β-glycosidic bonds are hydrolyzed through hyaluronidase and thehyaluronic acid is thus decomposed into smaller fragments. Commerciallyavailable hyaluronic acid—usually as a potassium salt—is isolated fromhuman umbilical cords or cockscombs, but is increasingly manufactured inbiotechnology through bacterial fermentation.

Methods known from the literature are used for modifying hyaluronicacid, i.e., preparing hyaluronic acid derivatives (e.g., Danishefsky,Arch. Biochem. Biophys., 90, 1960, p. 114 et seq.; Nagasawa, Carbohydr.Res., 58, 1977, p. 47 et seq.; Ayotte, Carbohydr. Res. 145, 1986, p. 267et seq.; Ogamo, Carbohydr. Res. 193, 1989, p. 165 et seq.; Jesaja, Can.J. Chem.; 67, 1989, p. 1449 et seq.; Mulloy, Carbohydr. Res. 255, 1994,p.1 et seq.). These are regioselective and stereoselective andnon-regioselective and non-stereoselective (static) reactions. Based onthese methods, hyaluronic acid may particularly be altered through N andO desulfation, O desulfation, 6-O desulfation, deacetylation, oracetylation, as well as sulfation and acylation with aliphatic oraromatic residues. In particular, through the known methods, aminogroups and sulfate or carboxyl residues may be introduced by usingprotective group chemistry and known, partially regioselective reactionsof organic chemistry.

As defined in the present invention, the term “hyaluronic acidderivatives” is understood to include all reaction products which arestructurally changed from the starting product through targetedmodifications of natural hyaluronic acid. Furthermore, the term“hyaluronic acid and hyaluronic acid derivatives” is understood toinclude all polyelectrolytic salts thereof, e.g., sodium, potassium,magnesium, and potassium salts. The listed reactions and further knownreactions of organic chemistry for reacting the functional groups ofhyaluronic acid are considered “modifications” as defined in the presentinvention.

Hyaluronic acid, the hyaluronic acid derivatives, and chitosan may beimmobilized on the implant covalently and/or through physisorption asindividual substances, copolymers or block polymers of hyaluronic acid,hyaluronic acid derivatives, and chitosan, and also in the form ofmixtures of the above-mentioned individual substances and polymers.

Covalent bonding of the polysaccharide layer to the surface of theimplant is preferably performed through single-point or multipointsuspension on spacers. Furthermore, mechanical and/or chemicalstabilization of the coating material against enzymatic and hydrolyticdegradation and also against mechanical stress is preferably achievedthrough cross-linking of a previously applied (primary) polysaccharidelayer. The immobilization of the polysaccharide layer on the surface ofthe implants may be performed according to known methods ofimmobilization of enzymes, methods of membrane manufacturing, plasticprocessing, polymer chemistry, peptide, protein, and sugar chemistry viacovalent bonds with and without the use of spacers, using single pointand multipoint suspension, and point suspension as a monolayer ormultilayer or with additional stabilization through cross-linking.

A coating having a layer thickness in the range between 10-400 μm,particularly 50-120 μm, has been shown to be advantageous. At the citedlayer thicknesses, no significant effect on the functionality of theimplant could be determined.

Furthermore, the hyaluronic acid or the hyaluronic acid derivatives mayhave an average molecular weight in the range from approximately300,000-500,000, particularly 380,000-420,000 g/mole aftersterilization. The intrinsic therapeutic effect of hyaluronic acid andits derivatives reach a maximum in the claimed molecular weight range(Papkonstantinou, G. Karakulakis, O. Eickelberg, A. P. Perruchoud, L. H.Block, and M. Roth; A 340 kDa hyaluronic acid secreted by human vascularsmooth muscle cells regulates their proliferation and migration,Glycobiology 1998, 8, 821-830).

A further advantageous aspect of the teaching according to the presentinvention is the targeted influencing of the in vivo degradationbehavior of the biopolymer. The term “degradation behavior” isunderstood to include degradation of the polysaccharide layer accordingto the present invention occurring through chemical, thermal, oxidative,mechanical, or biological processes in the living organism over time. Itis to be ensured that at least in the first weeks after theimplantation, local occurrences of inflammation of the adjoining tissueare reduced or even avoided. However, the coating is to prevent or atleast significantly suppress surface adsorption of high-molecular-weightbiomolecules on the implant over a specific period of time.

The polysaccharide layer may have a composition such that the in vivodegradation of the polysaccharide layer is slowed from the outside inthe direction of the main body of the implant. The degradation behaviormay be altered continuously or suddenly in this case. According to thelatter variation, the polysaccharide layer comprises at least twopartial layers having different degradation behaviors, the degradationbehavior within each partial layer being able to be fixed ascontinuously changeable or constant over the partial layer. Themanufacturing of coatings of this type may be performed with the aid ofspray and immersion coating methods known per se.

The polysaccharide layer may have a composition such that an externalarea of the polysaccharide layer, which faces away from the main body ofthe implant, is degraded within 100 days in vivo. The external area maybe 10 to 250 μm, particularly 50 to 150 μm thick. If the polysaccharidelayer comprises at least two partial layers having different degradationbehaviors, to achieve this goal, an external partial layer may bemodified in such a way that this external partial layer is degraded bymore than 50 weight-percent within 100 days in vivo. The externalpartial layer may be 10 to 250 μm, particularly 50 to 150 μm thick.

Surprisingly, it has also been shown that in the presence of thepolysaccharide layer according to the present invention, the surfaceadsorption of high-molecular-weight biomolecules on the implant is alsoprevented or at least significantly repressed. Therefore, thepolysaccharide layer preferably has a composition such that an internalarea of the polysaccharide layer, which faces toward the main body ofthe implant, is not completely degraded within two years in vivo. Theinternal area may be 3 to 50 μm, particularly 5 to 20 μm thick. If thepolysaccharide layer comprises at least two partial layers havingdifferent degradation behaviors, to achieve this goal, an internalpartial layer, which directly adjoins the surface of the main bodyunderneath it or possibly an intermediate layer applied thereto, may beparticularly modified in such a way that this internal partial layer isnot degraded by more than 20 weight-percent within two years. Theexternal partial layer may be 3 to 50 μm, particularly 5 to 20 μm thick.

To influence the degradation behavior, the degradation behavior ofhyaluronic acid and its derivatives may be influenced by cross-linking,among other things. For this purpose, reference is made in general tothe numerous methods described in the literature for performing theindividual cross-linking reactions and expressly to the objects of U.S.Pat. No. 4,582,865, U.S. Pat. No. 5,550,187, U.S. Pat. No. 5,510,121,and WO 00/46252. For example, cross-linking may be performed with theaid of the following reagents:

Formaldehyde, glutaraldehyde, divinyl sulfone, polyanhydrides,polyaldehydes, carbodiimides, epichlorohydrin, ethylene glycoldiglycidyl ether, butane diol diglycidyl ether, polyglycerolpolyglycidyl ether, polyethylene glycol diglycidyl ether, polypropyleneglycol diglycidyl ether, or bis or polyepoxy cross-linking agents, suchas 1,2,3,4-diepoxybutane or 1,2,7,8-diepoxyoctane.

The relationship between degree of cross-linking and degradationbehavior may be determined via typical testing methods. A differingdegree of cross-linking results in a differing swelling behavior of thepolysaccharide layer. The swelling behavior may be determinedgravimetrically, among other things. Furthermore, the degree ofcross-linking may also be determined through infrared spectroscopicanalysis of cross-linked hyaluronic acid films. The reference fordegradation may be produced through a GPC analysis, i.e., through molarmass determination of degraded hyaluronic acid, on eluents.

The influence of the cited modifications on the in vivo degradationbehavior is generally known. However, since the degradation behavior isa function of further geometric and physiological factors, among otherthings, individual adaptation of the system to the particularrequirements is typically necessary.

The coating may typically be applied to all known metallic implants. Thethin polysaccharide layer made of hyaluronic acid and/or hyaluronic acidderivatives and chitosan is deposited using typical spraying methods orfrom solution for this purpose.

The manufacturing in principle of a covalently adhering polysaccharidelayer is described in WO 00/56377, whose disclosure is incorporatedherein by reference in its entirety. A substrate surface is modifiedwith reactive functionalities for this purpose, activated hyaluronicacid is provided, and this is then bound covalently to the reactivefunctionalities under suitable conditions. The polysaccharide layeraccording to the present invention may be bound to the surface of theimplant in the same way.

Furthermore, DE 196 30 563 (U.S. Pat. No. 5,964,794) discloses a methodfor improving the adhesion of a coating as a result of reinforcedphysisorption and/or covalent binding. In a first step, a reactivefunctionality is produced on the substrate surface. The reactivefunctionality particularly comprises amines, aldehydes, sulfides,alcohols, acid halogenides, and isocyanates. The polysaccharide layeraccording to the present invention may then be bound covalently—usingcoupling methods known per se—to the cited functionality.

The coating system according to the present invention may besupplemented by embedding therapeutic active ingredients, which arereleased into the surrounding tissue through the gradual degradation ofthe coating and/or through diffusion.

Furthermore, the polysaccharide layer may comprise an adhesion-promotinglayer made of chitosan. The adhesion-promoting layer directly adjoinsthe main body and possibly the intermediate layer applied thereto.Surprisingly, it has been shown that very uniform and strongly adheringcoatings may be produced in the presence of such an adhesion-promotinglayer. In addition, chitosan is a material of natural origin andtherefore has good biocompatibility. The adhesion-promoting layer may be0.1 to 50 μm, particularly 1 to 10 μm thick and may be modified like thehyaluronic acid and its derivatives to influence its degradationbehavior. In particular, the adhesion-promoting layer may be implementedin such a way that it may act as the internal partial layer or internalarea of the polysaccharide layer in the above-mentioned definition.

According to a further preferred variation of the present invention, thepolysaccharide layer contains chitosan in at least partial areas orpartial layers. In this way, the adhesive capability of thepolysaccharide layer may be improved further and uniform coatings may beproduced on the often very complex geometries of the substrates.

The stability of the polysaccharide layer may be increased ifpolycationic charges are produced through quaternization of the aminefunctions of the chitosan. If hyaluronic acid and/or its derivatives isadded as a polyanionic preparation, Symplex gels form. The ion/ioninteraction between the components, which is already very strong, may beincreased further through cross-linking. A weight component of thechitosan of the total weight of the polysaccharide layer is not morethan 50% in one embodiment.

In the first weeks after the implantation of stimulation electrodes,generally a temporary stimulus threshold increase may be determined,which may be attributed to local occurrences of inflammation of theadjoining tissue. These occurrences of inflammation additionally resultin unfavorable ingrowth behavior of the stimulation electrodes, whichnegatively influences the stimulation properties of the system in thelong term. This problem may be corrected through the coating systemaccording to the present invention. Therefore, the use of the coatingsystem in this context is claimed.

Stents are implanted very frequently in the course of acute myocardialtreatment. However, renewed closure of the opened vessel (restenosis)often occurs in the course of time due to specific microbiologicalprocesses. This can be counteracted effectively using the coating systemaccording to the present invention. Therefore, the use of the coatingsystem in this context is claimed.

In the following, the present invention will be explained in greaterdetail on the basis of exemplary embodiments

Exemplary Embodiment 1 Chitosan as a Partial Layer

The following method descriptions are particularly suitable formanufacturing a coating system according to the present invention onstents or stimulation electrodes.

The implant surface was previously cleaned, degreased, and stirredlightly for 10 minutes at room temperature in a 0.5 to 2% acetic acidsolution having a chitosan concentration between 0.1% and 0.5%. Themolecular weight of the chitosan was between 100,000 g/mole and1,000,000 g/mole. The implant was subsequently removed and dried.

Alternatively, a thin layer made of chitosan may be applied to theimplant through spraying. For this purpose, a 0.5% chitosan solution in0.5% acetic acid was used. The previously cleaned implants were sprayed5 to 20 times at intervals of 15 to 30 seconds for 0.5 to 1.0 secondswith the aid of an airbrush gun, the implants being dried at 40° C. to70° C. between the spraying steps. The applied layers have a layerthickness of 1 μm to 10 μm.

After drying, the implant was laid in an aqueous solution of hyaluronicacid having a molecular weight of at least 1,000,000 g/mole with lightstirring for 10 minutes at room temperature. After removal and drying,the implant was immersed for at least 2 hours at approximately 30° C. to40° C. in a cross-linking agent solution of 2 to 4 ml glutaraldehyde ina water-acetone mixture. The cross-linking agent solution was thenreplaced and the cross-linking was continued for 2 hours. Theexperimental conditions also resulted in cross-linking of chitosan withglutaraldehyde. The acid-catalyzed reaction of aldehyde with the amineof the chitosan occurred with the formation of a Schiff base.

The implant was then washed multiple times with distilled water andreductively fixed using a diluted solution of sodium cyanoborohydrideand washed multiple times with deionized water. The posttreatmentresulted in reduction of the Schiff base and free aldehyde functions.After removal, the sample was dried for 24 hours at 50° C. in the dryingcabinet.

The chitosan functions as an adhesion-promoting agent, since chitosanitself is poorly soluble in the neutral range (blood). In addition, thechitosan is provided in cross-linked form and also forms a covalent bondto the applied hyaluronic acid layer through the cross-linking with theaid of the glutaraldehyde. The thin adhesion-promoting layer made ofchitosan of 0.1 μm to 50 μm, preferably 1 μm to 10 μm, does not resultin any significant impairment of the electrical transmission propertiesof the electrodes.

Exemplary Embodiment 2 Chitosan as an Additive

In addition to the polyanions hyaluronic acid and/or its hyaluronic acidderivatives, the coating system also contains the polycationic chitosan.A further functional group for the cross-linking agent glutaraldehyde isalso provided by the amine of the chitosan. The aldehyde function mayreact both with the amine function of the chitosan and also with thecarbonyl and/or hydroxyl function of the hyaluronic acid. The degree ofcross-linking may be increased further and the ionic interaction betweenthe polyanions and polycations may be additionally reinforced throughthese reactions. The layered system made of polyanions and polycationsmay be produced through alternating spraying of the implant withsolutions of desired concentrations of chitosan, hyaluronic acid, andhyaluronic acid derivatives.

For this purpose, previously cleaned implants are alternately sprayedwith an aqueous solution of hyaluronic acid or hyaluronic acidderivatives and chitosan dissolved in acetic acid. In this case, theconcentration of the hyaluronic acid or hyaluronic acid derivatives is0.1% to 1%, or 0.2 to 0.5%. The concentration of the acetic acid is 0.1%to 2%, or 0.5% to 1%. The concentration of the chitosan is 0.1% to 1%,or 0.2% to 0.5%. The molecular weight of the hyaluronic acid or thehyaluronic acid derivatives may be at least 1,000,000 g/mole and themolecular weight of the chitosan may be at least 100,000 g/mole. Bothsolutions are applied alternately to the implant with the aid of a spraymethod at intervals of 2 seconds to 60 seconds, preferably 15 seconds to30 seconds. The particular proportion of polyanions and polycations maybe set through the selection of the concentration of hyaluronic acidand/or chitosan and the particular spray duration. The weight componentof chitosan in the overall layer system is not more than 50%. The numberof spraying steps determines the layer thickness of the overall layersystem. Thus, with 60 spray steps having a spray duration of 0.5seconds, layer thicknesses between 5 μm and 10 μm, measured in the drystate, are achieved using typical airbrush guns. After the coating, theand subsequently immersed for at least 2 hours at approximately 30° C.to 40° C. in a cross-linking agent solution of 2 to 4 ml glutaraldehydein a water-acetone mixture. The cross-linking agent solution is thenreplaced for at least a further 2 hours. Subsequently, the implant iswashed multiple times using distilled water and reductively fixed usinga diluted solution of sodium cyanoborohydride, and washed multiple timesusing deionized water. After removal, the sample is dried for 24 hoursat 50° C. in the drying cabinet.

Investigations of the Swelling Behavior

Differing degrees of cross-linking result in differing swelling behaviorof the polysaccharide layer. The swelling behavior may be determinedgravimetrically, among other ways. Furthermore, the degree ofcross-linking may also be determined through infrared spectroscopicanalysis on cross-linked hyaluronic acid films. The reference fordegradation may be produced through a GPC analysis, i.e., through molarmass determination of degraded hyaluronic acid, on eluents.

In order to determine the influence of cross-linking parameters on thecross-linking and therefore also on the swelling behavior, theparameters of temperature, water content, type of cross-linking agent,and cross-linking duration were varied. Hyaluronic acid films were castand cross-linked to determine the correlation between swelling behaviorand the cross-linking parameters.

EXAMPLES 1 THROUGH 8 Experiments on the Swelling Behavior

The method according to Example 1 was divided into the following steps:

(a) preparing a 1% hyaluronic acid solution;

(b) pouring 3 ml 1% hyaluronic acid solution into Petri dishes having 4cm diameter and subsequent drying;

(c) adding 4 ml cross-linking agent solution to the films at roomtemperature (20° C.), the cross-linking agent solution comprising 240 mlacetone, 80 ml 25% glutaraldehyde solution, and 1.6 ml 3 molarhydrochloric acid;

(d) cross-linking duration 20 hours, the cross-linking agent solutionhaving been replaced after 4 hours;

(e) removal and washing with deionized water;

(f) adding 4 ml 2.2% NaBH₃CN solution;

(g) washing with deionized water;

(h) drying.

The further Examples 2 through 8 deviated as follows, with otherwiseidentical method control:

In Example 2, the cross-linking duration in step (d) was 4 hours withoutreplacement of the cross-linking agent solution.

In Example 3, the cross-linking duration in step (d) was 2 hours withoutreplacement of the cross-linking agent solution.

In Example 4, the cross-linking agent solution cited in step (c)additionally contained 20 ml deionized water.

In Example 5, the cross-linking agent solution cited in step (c)additionally contained 100 ml deionized water.

In Example 6, the cross-linking agent solution cited in step (c)contained 80 ml 25% formaldehyde solution instead of the glutaraldehydesolution.

In Example 7, the cross-linking in step (d) was performed at 30° C. andthe cross-linking duration in step (d) was 6.5 hours, the cross-linkingsolution having been replaced after 1.5 hours.

In Example 8, the cross-linking in step (d) was performed at 30° C. andthe cross-linking duration in step (d) was 7 hours, the cross-linkingsolution having been replaced after 2 hours.

After drying the cross-linked films, these were weighed and subsequentlywashed in deionized water for 30 minutes, blotted briefly and weighedagain in order to determine the swelling behavior, which correlates withthe degree of cross-linking.

The swelling factors determined may be inferred from the followingtable: TABLE 1 swelling factors Example 1 2 3 4 5 6 7 8 Swelling 6 14 757 7 34 10 13 factor

The exemplary experiments on cross-linking led to the followingconclusions:

The cross-linking duration has a significant influence on the degree ofcross-linking, which is reflected in the swelling behavior. At across-linking duration of only 2 hours, hyaluronic acid films wereobtained which were unstable and dissolved within a few hours in water.In contrast, at a cross-linking duration of 4 hours, stable hyaluronicacid films were obtained, which displayed a higher swelling factor thanthe films of the standard method, however. The water content of thecross-linking agent solution did not have a strong influence on theswelling factor, and therefore the degree of cross-linking, in the rangeexamined. The use of formaldehyde instead of glutaraldehyde resulted incross-linked hyaluronic acid films having a significantly higherswelling factor. This may possibly be attributed to the shorter chainlength of the formaldehyde. The shorter cross-linking agent formaldehydethus results in lightly cross-linked hyaluronic acid films.Cross-linking at a temperature of 30° C. and a cross-linking duration of7 hours results in hyaluronic acid films having a somewhat higherswelling factor and therefore a lower degree of cross-linking.

1. A coating system for implants having a metallic main body, which isoptionally covered with one or more intermediate layers, and in whichthe coating system comprises a coating applied thereto to increase thetissue compatibility, wherein the coating comprises a polysaccharidelayer made of (a) chitosan and (b) hyaluronic acid and/or hyaluronicacid derivatives.
 2. The coating system according to claim 1, whereinthe polysaccharide layer contains chitosan in partial areas or partiallayers.
 3. The coating system according to claim 2, wherein thepolysaccharide layer comprises an adhesion-promoting layer made ofchitosan.
 4. The coating system according to claim 3, wherein theadhesion-promoting layer is 0.1 to 50 μm thick.
 5. The coating systemaccording to claim 1, wherein a component of the chitosan in the totalweight of the polysaccharide layer is not more than 50 weight-percent.6. The coating system according to claim 1, wherein the hyaluronic acidand hyaluronic acid derivatives have an average molecular weight between300,000 and 500,000 Dalton after sterilization of the implant.
 7. Thecoating system according to claim 6, wherein the average molecularweight is between 380,000 and 420,000 Dalton.
 8. The coating systemaccording to claim 1, wherein the polysaccharide layer has a compositionsuch that the in vivo degradation of the polysaccharide layer is slowedfrom the outside in the direction of the main body of the implant. 9.The coating system according to claim 8, wherein an internal area of thepolysaccharide layer is not degradable, at least completely, within twoyears.
 10. The coating system according to claim 9, wherein the internalarea is 3 to 50 μm thick.
 11. The coating system according to claim 8,wherein an external area of the polysaccharide layer is degradable invivo within 100 days.
 12. The coating system according to claim 11,wherein the external area is 10 to 250 μm thick.
 13. The coating systemaccording to claim 8, wherein the polysaccharide layer comprises atleast two partial layers having different degradation behaviors, thedegradation behavior within each partial layer being able to be fixedcontinuously changeably or constant over the partial layer.
 14. Thecoating system according to claim 13, wherein the polysaccharide layercomprises an internal partial layer which is degradable by not more than20 weight-percent in vivo within 2 years.
 15. The coating systemaccording to claim 14, wherein the internal partial layer is 3 to 50 μmthick.
 16. The coating system according to claim 13, wherein thepolysaccharide layer comprises an external partial layer which isdegradable by at least more than 50 weight-percent within 100 days invivo.
 17. The coating system according to claim 16, wherein the externalpartial layer is 10 to 250 μm thick.
 18. The coating system according toclaim 8, wherein a layer thickness of the polysaccharide layer isbetween 10-400 μm.
 19. The coating system according to claim 18, whereinthe layer thickness is 50-120 μm.
 20. The coating system according toclaim 8, wherein the hyaluronic acid, the hyaluronic acid derivatives,and the chitosan are components of the polysaccharide layer asindividual substances, copolymers, or block polymers made of hyaluronicacid, hyaluronic acid derivatives, and chitosan, or in the form ofmixtures of the above-mentioned individual substances.
 21. The coatingsystem according to claim 1, wherein the polysaccharide layer isimmobilized covalently or through physisorption on the implant. 22.(canceled)
 23. (canceled)
 24. An endovascular implant comprising thecoating system of claim
 1. 25. An implantable tissue stimulatorcomprising the coating system of claim 1.